Stress, drug cue exposure and cocaine itself potently stimulate stress and reward systems in the brain and each increase drug craving, thereby increasing the susceptibility to relapse. Women, in particular, show a greater stress and negative affect related susceptibility to relapse. Previous SCOR-related research shows clear sex differences in stress responses, behavioral effects of cocaine and in negative affect and anxiety associated with cocaine craving and stress related relapse susceptibility. However, no previous research has examined the basis of sex differences in stress and cue induced craving and arousal, both of which are known to increase relapse susceptibility. Cumulating evidence suggest that gonadal hormones, estradiol (E) and progesterone (P), may contribute to these sex differences. While E enhances behavioral responses to cocaine, P attenuates subjective, behavioral and physiological responses to cocaine. Whether gonadal hormones such as progesterone affect stress and drug cue-induced craving, and mediate vulnerability to cocaine relapse, especially in women has been studied thus far. Our preliminary findings in cocaine dependent women suggested that high levels of luteal phase P was associated with decreases in stress and drug cue-induced drug seeking, anxiety and blood pressure responses. On the basis of these data, we hypothesize that progesterone treatment vs. placebo will decrease stress and drug cue-induced cocaine craving, negative affect and alter physiological and HPA responses to stress, and these changes will be greater in women than men. In a sample of 120 treatment-seeking cocaine dependent men and women (60 men and 60 women), the following specific aims are proposed: (1) to examine if progesterone alters stress and cue-induced craving, anxiety and negative emotion responses in cocaine dependent men and women, with sex differences in these effects; (2) To assess progesterone's sex-specific effects on HPA axis measures (ACTH, cortisol and prolactin) during stress and drug cue exposure; (3) To examine progesterone's sex-specific effects on cardiovascular responses to stress and drug cue exposure and to assess its effects on plasma catecholamines; (4) To explore whether progesterone's effects on craving, HPA axis and sympathetic responses are associated with neuroactive steroids and whether these are differentially affected in men and women. Findings from this study will (A) provide a greater understanding of the effects of progesterone, a key gonadal hormone, and it's role in stress regulation, stress-related cocaine seeking and relapse vulnerability, and (B)contribute crucial information needed to develop progesterone as a potential pharmacotherapy to prevent stress-related cocaine relapse in women.